Cyclobutaindolecarboxamide compounds

ABSTRACT

A compound selected from those of formula (I):  
                 
 
     wherein:  
     n represents integer from 0 to 6,  
     R 1  represents a group selected from hydrogen, hydroxy, cyano, alkoxy, alkoxycarbonyl, carboxy, optionally substituted aminocarbonyl, and NR 4 R 5  wherein R 4 , and R 5  are as defined in the description,  
                 
 
      represents a group selected from hydrogen, alkyl, hydroxymethyl, and —U—V—W wherein T, U, V, and W are as defined in the description, and  
     R 3  represents a group selected from hydrogen, linear or branched (C 1 -C 6 )alkyl, aryl, and, heteroaryl,  
     its isomers, and also addition salts thereof with a pharmaceutically-acceptable acid or base, and medicinal products containing the same are useful in the treatment of CNS disorders.

FIELD OF THE INVENTION

[0001] The present invention relates to new cyclobutaindolecarboxamidecompounds, and pharmaceutical compositions containing them.

[0002] The compounds of the present invention are useful in thetreatment of disorders of the central nervous system, such as anxiety,panic attacks, obsessive-compulsive disorders, phobias, impulsivedisorders, drug abuse, cognitive disorders, psychoses, depression andmood disorders.

PRIOR ART DESCRIPTION

[0003] Numerous polycyclic and heterocyclic compounds containing a ureafunction have been described in the literature as antagonists of variousserotonergic receptors, thus enabling them to be used in the treatmentof disorders of the central nervous system. This applies more especiallyto the Patent Applications WO 95/29177, WO 96/23783 and WO 98/47868,while patent specification U.S. 5,514,690 describesaminocarbonylquinoline and indoline compounds and claims them for theirproperty of activating potassium pumps.

[0004] In addition to being new, the compounds of the present inventionhave proved very active in the treatment of disorders of the centralnervous system, and more especially have demonstrated strong activity inthe Vogel conflict test in the rat, and in the marble-burying test inthe mouse. The results obtained in the first test allows the use of thecompounds of the invention in the treatment of clinical phenomenaassociated with anxiety to be proposed, and the results obtained in thesecond test demonstrates the strong therapeutic potential of thecompounds of the invention in the treatment of illnesses associated withmood disorders.

DETAILED DESCRIPTION OF THE INVENTION

[0005] The invention relates more especially to the compounds of formula(I):

[0006] wherein:

[0007] n represents an integer of from 0 to 6,

[0008] R₁ represents a group selected from hydrogen, hydroxy, cyano,linear or branched (C₁-C₆)alkoxy, linear or branched(C₁-C₆)alkoxycarbonyl, carboxy, aminocarbonyl (the amino moietyoptionally being substituted by one or two identical or different groupsselected from linear or branched (C₁-C₆)alkyl, aryl andaryl-(C₁-C₆)alkyl in which the alkyl moiety may be linear or branched)and NR₄R₅ wherein R₄ and R₅, which may be identical or different,represent a group selected from linear or branched (C₁-C₆)alkyl, aryl,aryl-(C₁-C₆)alkyl in which the alkyl moiety may be linear or branched,heteroaryl, heteroaryl-(C₁-C₆)alkyl in which the alkyl moiety may belinear or branched, cycloalkyl, cycloalkyl-(C₁-C₆)alkyl in which thealkyl moiety may be linear or branched, linear or branched(C₂-C₆)alkenyl and linear or branched (C₂-C₆)alkynyl,

[0009] R₂ represents a group selected from hydrogen, linear or branched(C₁-C₆)alkyl, hydroxymethyl, a group of formula

[0010]  and —U—V—W

[0011] wherein:

[0012] T represents a monocyclic or polycyclic (C₃-C₁₂)cycloalkyl group,it being possible for one of the carbon atoms of the cycloalkyloptionally to be replaced by a group selected from oxygen, selenium, agroup of formula S(O)_(p) wherein p represents an integer of from 0 to 2inclusive, and a group of formula SiR₆R₇ wherein R₆ and R₇, which may beidentical or different, represent a linear or branched (C₁-C₆)alkylgroup,

[0013] U represents a bond or a methylene group,

[0014] V represents a bond, an oxygen atom or a group S(O)_(q) wherein qis an integer of from 0 to 2 inclusive, and

[0015] W represents a group selected from aryl, aryl-(C₁-C₆)alkyl inwhich the alkyl moiety may be linear or branched, cycloalkyl, andcycloalkyl-(C₁-C₆)alkyl in which the alkyl moiety may be linear orbranched, and

[0016] R₃ represents a group selected from hydrogen, linear or branched(C₁-C₆)alkyl, aryl and heteroaryl,

[0017] to their isomers, and also to addition salts thereof with apharmaceutically acceptable acid or base.

[0018] An aryl group is to be understood as a group selected fromphenyl, biphenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl,indanyl, indenyl and benzocyclobutyl, each of which groups is optionallysubstituted by one or more identical or different groups selected fromhalogen atoms, linear or branched (C₁-C₆)alkyl, hydroxy, linear orbranched (C₁-C₆)-alkoxy, nitro, cyano, linear or branched(C₁-C₆)trihaloalkyl, amino, monoalkylamino, di-(C₁-C₆)alkylamino inwhich the alkyl moieties may be linear or branched,(C₁-C₆)-trihaloalkoxy in which the alkoxy moiety may be linear orbranched, amino-(C₁-C₆)alkylaminocarbonyl (the nitrogen atoms of each ofthe amino moieties optionally being substituted by identical ordifferent linear or branched (C₁-C₆)alkyl groups), pyridyl, pyridyloxyand pyridyloxymethyl, the latter three groups optionally beingsubstituted by a linear or branched (C₁-C₆)alkyl group.

[0019] A heteroaryl group is to be understood as an aromatic monocyclicsystem, or a bicyclic system in which one of the rings is aromatic andthe other ring is aromatic or partially hydrogenated, having from 5 to12 ring members and containing one, two or three identical or differenthetero atoms selected from oxygen, nitrogen and sulphur, each of thegroups optionally being substituted by one or more identical ordifferent groups selected from the substituents described for the arylgroup defined above.

[0020] A cycloalkyl group is to be understood as a mono- or poly-cyclicsystem having from 3 to 12 ring members and optionally containing one ormore unsaturations, wherein the unsaturations do not confer an aromaticcharacter to the said ring system.

[0021] Isomers is to be understood as optical isomers (enantiomers(enantiomers and diastereoisomers).

[0022] Amongst the pharmaceutically acceptable acids there may bementioned, without implying any limitation, hydrochloric, hydrobromic,sulphuric, phosphonic, acetic, trifluoroacetic, lactic, pyruvic,malonic, succinic, glutaric, fumaric, tartaric, maleic, citric,ascorbic, oxalic, methanesulphonic, camphoric acid, etc. . .

[0023] Amongst the pharmaceutically acceptable bases there may bementioned, without implying any limitation, sodium hydroxide, potassiumhydroxide, triethylamine, tert-butylamine etc. . .

[0024] According to an advantageous embodiment of the invention,preferred compounds of the invention are compounds of formula (I)wherein R₂ represents a hydrogen atom.

[0025] According to another advantageous embodiment of the invention,preferred compounds of the invention are compounds of formula (I)wherein R₂ represents a group of formula

[0026] wherein T is as defined for formula(I), n is 1, and R₁ representsa cyano group or an amino group optionally substituted by one or twoidentical or different groups selected from linear or branched(C₁-C₆)alkyl and aryl-(C₁-C₆)alkyl in which the alkyl moiety may belinear or branched.

[0027] In another advantageous embodiment, preferred compounds of theinvention are compounds of formula (I) wherein n is 0, R₁ represents ahydrogen atom or a cyano group and R₂ represents a group of formula—U—V—W wherein U represents a single bond, V represents a group offormula S(O)_(p) wherein p is as defined for formula (I) and Wrepresents an aryl group.

[0028] Especially advantageously, preferred compounds of the inventionare compounds of formula (I) wherein n is 0, R₁ represents a hydrogenatom or a cyano group and R₂ represents a hydrogen atom.

[0029] The substituent R₃ preferred in accordance with the invention isthe heteroaryl group and, more especially, the pyridyl group.

[0030] The following are preferred compounds of the invention:

[0031]N-(3-pyridyl)-2,3,5,6-tetrahydro-1H-cyclobuta[f]indole-1-carboxamide,

[0032]5-cyano-N-(3-pyridyl)-2,3,5,6-tetrahydro-1H-cyclobuta[f]indole-1-carboxamide,

[0033]6-cyano-N-(3-pyridyl)-2,3,5,6-tetrahydro-1H-cyclobuta[f]indole-1-carboxamide,

[0034]6-(hydroxymethyl)-N-(3-pyridyl)-2,3,5,6-tetrahydro-1H-cyclobuta[f]indole-1-carboxamide,

[0035]5-(hydroxymethyl)-N-(3-pyridyl)-2,3,5,6-tetrahydro-1H-cyclobuta[f]indole-1-carboxamide,

[0036]7-cyano-N-(3-pyridyl)-1,2,6,7-tetrahydro-3H-cyclobuta[e]indole-3-carboxamide,

[0037]7-(hydroxymethyl)-N-(3-pyridyl)-2,3,6,7-tetrahydro-1H-cyclobuta[g]indole-1-carboxamide,

[0038]6-[(dimethylamino)methyl]-6-(1-hydroxycyclohexyl)-N-(3-pyridyl)-2,3,5,6-tetrahydro-1H-cyclobuta[f]indole-1-carboxamide,

[0039]6-cyano-6-(phenylsulphanyl)-N-(3-pyridyl)-2,3,5,6-tetrahydro-1H-cyclobuta[f]indole-1-carboxamide,

[0040]6-cyano-6-cyclohexyl-N-(3-pyridyl)-2,3,5,6-tetrahydro-1H-cyclobuta[f]indole-1-carboxamide,

[0041]6-cyclohexyl-N-(3-pyridyl)-2,3,5,6-tetrahydro-1H-cyclobuta[f]indole-1-carboxamide,

[0042]6-cyano-N-{6-[(2-methyl-3-pyridyl)oxy]-3-pyridyl}-6-(phenylsulphanyl)-2,3,5,6-tetrahydro-1H-cyclobuta[f]indole-1-carboxamide.

[0043] The isomers of the preferred compounds, and also the additionsalts with a pharmaceutically acceptable acid or base of the preferredcompounds, form an integral part of the invention.

[0044] The invention relates also to a process for the preparation ofthe compounds of formula (I), which is characterised in that there isused as starting material a compound of formula (Il):

[0045] wherein R′₁ represents a group selected from hydrogen, cyano,hydroxymethylene, carboxy and linear or branched (C₁-C₆)alkoxycarbonyl,which compound of formula (II) is reacted, under the conditions ofreductive amination, with a compound of formula (III):

(AO)₂CHCHO  (III)

[0046] wherein A represents a linear or branched (C₁-C₆)alkyl group, toyield the compounds of formula (IV):

[0047] wherein A and R′₁ are as defined hereinbefore, which compounds offormula (IV) are treated with a compound of formula (V):

ClSO₂E  (V)

[0048] wherein E represents a linear or branched (C₁-C₄)alkyl group,phenyl or p-toluyl, to yield the compounds of formula (VI):

[0049] wherein A, E and R′₁ are as defined hereinbefore, which compoundsof formula (VI) are cyclised under acid conditions to yield thecompounds of formula (VII):

[0050] wherein E and R′₁ are as defined hereinbefore, which compounds offormula (VII) are treated either with an alkali metal hydroxide in analcoholic solvent or with sodium in liquid ammonia to yield thecompounds of formula (VIII):

[0051] wherein R′₁ is as defined hereinbefore, which compounds offormula (VIII) are then reduced, in accordance with the conventionalconditions of organic synthesis, to yield the compounds of formula (IX):

[0052] wherein R′₁ is as defined hereinbefore, which compounds offormula (IX) are treated with an isocyanate of formula (X):

R₃—N═C═O  (X)

[0053] wherein R₃ is as defined for formula (I), to yield the compoundsof formula (I/a), a particular case of the compounds of formula (I):

[0054] wherein R′₁ and R₃ are as defined hereinbefore, or whichcompounds of formula (IX), in the case where R′₁ represents a cyanogroup, are treated:

[0055] either with a ketone of formula (XI):

[0056] wherein T is as defined for formula (I), to yield the compoundsof formula (XII):

[0057] wherein T is as defined hereinbefore, which compounds of formula(XII) are then:

either treated with an isocyanate of formula (X) as describedhereinbefore to yield the compounds of formula (I/b), a particular caseof the compounds of formula (I),

[0058] wherein T and R₃ are as defined hereinbefore,

or, after protection of the amine of the indoline group, reducedaccording to the conventional methods of organic synthesis to yield thecompounds of formula (XIII):

[0059] wherein T is as defined hereinbefore and P₁ is a conventionalprotecting group, the primary amine function of which compounds offormula (XIII) is then substituted and converted into the secondary andthen tertiary amine function, using conventional methods of organicchemistry, to yield the compounds of formula (XIV):

[0060] wherein R₄ and R₅ are as defined for formula (I) and T and P₁ areas defined hereinbefore, which compounds of formula (XIV), afterdeprotection of the nitrogen atom of the indoline nucleus, are treatedwith a compound of formula (X) as described hereinbefore to yield thecompounds of formula (I/c), a particular case of the compounds offormula (I):

[0061] wherein T, R₄, R₅ and R₃ are as defined hereinbefore,

[0062] or with a strong base or an alkali metal alcoholate, in thepresence of a compound of formula (XV):

W₁—X  (XV)

[0063] wherein W₁ represents a linear or branched (C₁-C₆)alkyl group, anaryl-(C₁-C₆)alkyl group in which the alkyl moiety may be linear orbranched, a cycloalkyl group, or a cycloalkyl-(C₁-C₆)alkyl group inwhich the alkyl moiety may be linear or branched, and X represents aleaving group, such as a halogen atom or a trifluoromethylsulphonate,mesylate or tosylate group, to yield the compounds of formula (XVI):

[0064] wherein W₁ is as defined hereinbefore, which compounds of formula(XVI) are:

either treated with a compound of formula (X) as described hereinbeforeto yield the compounds of formula (I/d), a particular case of thecompounds of formula (I):

[0065] wherein W₁ and R₃ are as defined hereinbefore,

or, after protection of the nitrogen atom of the indoline nucleus,converted like the compounds of formula (XII) to primary, secondary andthen tertiary amine to yield, after deprotection and treatment in thepresence of a compound of formula (X) as described hereinbefore, thecompounds of formula (I/e), a particular case of the compounds offormula (I):

[0066] wherein W₁, R₃, R₄ and R₅ are as defined hereinbefore,

[0067] or with bromine in a chlorine-containing organic solvent to yieldthe compounds of formula (XVII):

[0068] which compounds of formula (XVII) are reacted with a compound offormula (XVIII):

W—V₁—H  (XVIII)

[0069] wherein W is as defined for formula (I) and V₁ represents anoxygen atom or a sulphur atom, to yield the compounds of formula (XIX):

[0070] wherein V₁ and W are as defined hereinbefore, which compounds offormula (XIX) are:

either treated with a compound of formula (X) as described hereinbeforeto yield the compounds of formula (I/f), a particular case of thecompounds of formula (I):

[0071] wherein R₃, V₁ and W are as defined hereinbefore, which compoundsof formula (I/f), in the case where V₁ represents a sulphur atom, may besubjected to oxidation under conventional conditions of organicsynthesis to yield the compounds of formula (I/g), a particular case ofthe compounds of formula (I):

[0072] wherein R₃ and W are as defined for formula (I) and q₁ is aninteger of from 1 to 2 inclusive,

or protected and then converted, by the same sequence of reactions asthe compounds of formula (XII), to primary, secondary and tertiary amineto yield, after deprotection and treatment with a compound of formula(X), as described hereinbefore, the compounds of formula (I/h), aparticular case of the compounds of formula (I):

[0073] wherein V₁, W, R₃, R₄ and R₅ are as defined hereinbefore, whichcompounds of formula (I/h), in the case where V₁ represents a sulphuratom, may be subjected to oxidation under conventional conditions oforganic synthesis to yield the compounds of formula (I/i), a particularcase of the compounds of formula (I):

[0074] wherein W, R₃, R₄, R₅ and q₁ are as defined hereinbefore,

[0075] or with an alkali metal hydride in dimethylformamide, in thepresence of formaldehyde, to yield the compounds of formula (XX):

[0076] which compounds of formula (XX) are:

either treated with a compound of formula (X) as described hereinbeforeto yield the compounds of formula (I/j), a particular case of thecompounds of formula (I):

[0077] wherein R₃ is as defined for formula (I),

or protected at the nitrogen atom of the indoline nucleus, then treatedaccording to Mitsunobu reaction conditions with a compound of formula(XXI):

W—OH  (XXI)

[0078] wherein W is as defined for formula (I), to yield, afterdeprotection of the nitrogen atom of the indoline nucleus, the compoundsof formula (XXII):

[0079] wherein W is as defined hereinbefore, which compounds of formula(XXII) are:

[0080] either treated with a compound of formula (X) as describedhereinbefore to yield the compounds of formula (I/k), a particular caseof the compounds of formula (I):

[0081] wherein R₃ and W are as defined hereinbefore,

[0082] or protected and then converted, by the same reaction sequence asthe compounds of formula (XII), to primary, secondary and tertiary amineto yield, after deprotection and treatment with a compound of formula(X), as described hereinbefore, the compounds of formula (I/l), aparticular case of the compounds of formula (I):

[0083] wherein R₃, R₄, R₅ and W are as defined hereinbefore, thecompounds (I/a) to (I/l) constituting the totality of the compounds ofthe invention, which compounds are purified, if necessary, according toa conventional purification technique, may be separated, if desired,into their different isomers according to a conventional separationtechnique, and are converted, if desired, into addition salts with apharmaceutically acceptable acid or base.

[0084] The compounds of formulae (II), (III), (V), (X), (XI), (XV),(XVIII) and (XXI) are either known products, or products obtained fromknown substances according to conventional procedures in organicchemistry.

[0085] In view of their pharmacological properties, the compounds of thepresent invention are useful as medicaments in the treatment of anxiety,panic attacks, obsessive-compulsive disorders, phobias, impulsivedisorders, drug abuse, cognitive disorders, psychoses, depression, andmood disorders.

[0086] The present invention relates also to pharmaceutical compositionscomprising as active ingredient at least one compound of formula (I), anoptical isomer thereof or an addition salt thereof with apharmaceutically acceptable acid or base, alone or in combination withone or more pharmaceutically acceptable, inert, non-toxic excipients orcarriers.

[0087] Among the pharmaceutical compositions according to the inventionthere may be mentioned more especially those which are suitable fororal, parenteral (intravenous, intramuscular or subcutaneous) per- ortrans-cutaneous, nasal, rectal, perlingual, ocular or respiratoryadministration, and especially tablets or dragees, sublingual tablets,soft gelatin capsules, hard gelatin capsules, suppositories, creams,ointments, dermal gels, injectable or drinkable preparations, aerosols,eye or nose drops, etc. . .

[0088] The useful dosage varies in accordance with the age and weight ofthe patient, the administration route, the nature and severity of thedisorder and the administration of possible associated treatments andranges from 0.5 mg to 25 mg in one or more administrations per day.

[0089] The following Examples illustrate the invention but do not limitit in any way. The starting materials used are known products orproducts prepared according to known procedures. The variousPreparations result in synthesis intermediates for use in thepreparation of the compounds of the invention

[0090] The structures of the compounds described in the Examples weredetermined according to customary spectrophotometric techniques(infrared, nuclear magnetic resonance, mass spectrometry, . . . ).

[0091] The melting points were determined using either a Kofler hotplate (K.), or a hot plate under microscope (M.K.). Where the compoundexists in salt form, the melting point given corresponds to that of theproduct in salt form.

[0092] For information only, the numbering used for the tricyclicsystems is as follows:

PREPARATION 1: 2,3,5,6-Tetrahydro-1H-cyclobuta[f]lindole-6-carbonitrileStep 1: 5-[(2,2-Dimethoxyethyl)amino]benzocyclobutane-1-carbonitrile

[0093] To a suspension of 13.5 g of5-aminobenzocyclobutane-1-carbonitrile in 400 ml of 1,2-dichloroethanethere are added rapidly dropwise 26.5 ml of a 45% solution of2,2-dimethoxyacetaldehyde in tert-butyl methyl ether, followed by 16 mlof acetic acid and then, in portions, 39.7 g of sodiumtriacetoxyborohydride. After increasing the temperature to 29° C., thereaction mixture is brought to ambient temperature, stirred for 1 hour15 minutes and then hydrolysed by pouring the mixture into 500 ml of asaturated aqueous solution of NaHCO₃. The organic phase is removed,washed with water, and concentrated under reduced pressure to yield thedesired product.

Step 2:5-[N-(2,2-Dimethoxyethyl)-N-(metliyisulphonyl)amino]benzocyclohutane-1-carbonitrile

[0094] 10.8 ml of mesyl chloride are added in the course of 20 minutesto a solution, cooled to 0° C., of 21.6 g of the product obtained inStep 1, 58 ml of pyridine and 225 ml of dichloromethane. After stirringfor 40 minutes at 0° C., and then for 20 hours at ambient temperature,the reaction mixture is poured into 40 ml of a saturated aqueoussolution of NaHCO₃. After decanting and extracting twice with 150 ml ofdichloromethane each time, the combined organic phases are washed with1N hydrochloric acid, dried, and then concentrated under reducedpressure to yield the expected product.

Step 3:1-(Methylsulphonyl)-5,6-dihydro-1H-cyclobutafflindole-6-carbonitrile

[0095] In the course of 1 hour 15 minutes, a solution of 10.9 ml oftitanium chloride in 450 ml of toluene and a solution of 27.9 g of theproduct obtained in Step 2 in 450 ml of toluene are simultaneouslypoured into 2 litres of toluene at reflux. When the addition iscomplete, the temperature is allowed to drop to 40° C., and the whole isthen poured into 1.8 litres of a saturated aqueous solution of NaHCO₃.After decanting, the aqueous phase is extracted with toluene, and theorganic phases are combined, washed, dried and concentrated. The residueis purified by chromatography on silica gel(dichloromethane/cyclohexane: 75/25) allowing the expected product andits regioisomer to be isolated.

[0096] Melting point: 142-144° C. (M.K.)

Step 4: 5,6-Dihydro-1H-cyclobuta[f]indole-6-carbonitrile

[0097] 2.6 g of the product obtained in Step 3 are introduced into asolution of 7.7 g of potassium hydroxide in 190 ml of methanol. After 12hours at reflux, the methanol is evaporated off and the residue is takenup in ether. After washing, the organic phase is dried and concentratedto yield the expected product.

[0098] Melting point: 126-128° C. (M.K.)

Step 5: 2,3,5,6-tetrahydro-1H-cyclobutafflindole-6-carbonitrile

[0099] 3.43 g of the product obtained in Step 4 are dissolved in 55 mlof acetic acid. In the course of 5 minutes, 3.84 g of sodiumcyanoborohydride are added in portions to the reaction mixture, whichhas been cooled to 13° C. After returning to ambient temperature,stirring is carried out for 2 hours, and then the reaction mixture iscooled to 0° C. and the pH is adjusted to 11 by the addition of asolution of sodium hydroxide (45 g in 250 ml of water). The milkysolution obtained is extracted with ether. The organic phases arewashed, dried and concentrated to yield the expected product.

[0100] Melting point: 85-87° C. (M.K.)

PREPARATION 2: 2,3,6,7-Tetrahydro-1H-cyclobuta[e]indole-7-carbonitrileStep 1: 6,7-Dihydro-3H-cyclobuta[e]indole-7-carbonitrile

[0101] The product is obtained in accordance with the procedure in Step4 of Preparation 1, using as substrate the regioisomer obtained in Step3 of Preparation 1.

Step 2: 2,3,6,7-Tetrahydro-1H-cyclobuta[e]indole-7-carbonitrile

[0102] Starting from the compound obtained in Step 1, the product isobtained in accordance with the procedure in Step 5 of Preparation 1.

PREPARATION 3: 2,3,5,6Tetrahydro-1H-cyclobuta[f]indole Step 1:4-[(2,2-Dimethoxyetiyl)amino]benzocyclobutane

[0103] A solution of 1 g of the product obtained in Step 1 ofPreparation 1 in 20 ml of tetrahydrofuran and 0.22 ml of anhydrousethanol is added, at −70° C., to 40 ml of liquid ammonia. 322 mg ofsodium are then added in portions and stirring is carried out for 20minutes at −70° C. The reaction is terminated by the addition of 1.72 gof NH₄Cl, and all of the ammonia is evaporated off. The reaction mixtureis taken up in a saturated NH₄Cl solution and then extracted with ether.The organic phase is subsequently dried and concentrated to yield theexpected product.

Step 2: 2,3,5,6-Tetrahydro-1H-cyclobuta[f]indole

[0104] The product is obtained in accordance with the procedure inPreparation 1, Steps 2 to 5.

[0105] Melting point: 68-70° C.

PREPARATION 4: 2,3,5,6Tetrahydro-1H-cyclobuta[f]indol-6-ylmethanol Step1: Methyl 5-amino-1-benzocyclobutanecarboxylate

[0106] 9.74 g of methyl 5-nitro-1-benzocyclobutanecarboxylate arehydrogenated for 6 hours 30 minutes, at ambient temperature andatmospheric pressure, in the presence of 10% Pd/C. After filtration andconcentration under reduced pressure, the expected product is isolated.

Step 2: Methyl5-[(2,2-dimethoxyethyl)amino]-1-benzocyclobutanecarboxylate

[0107] Starting from the compound of the above Step, the product isobtained in accordance with the procedure in Step 1 of Preparation 1.

Step 3: Methyl5-[N-(2,2-dimethoxyethyl)-N-(methylsulphonyl)amino]-1-benzo-cyclobutanecarboxylate

[0108] Starting from the compound of the above Step, the product isobtained in accordance with the procedure in Step 2 of Preparation 1.

Step 4: Methyll-(metlhylsulphonyl)-5,6-dihydro-1H-cyclobuta[f]indole-6-carboxylate

[0109] Starting from the compound of the above Step, the product isobtained in accordance with the procedure in Step 3 of Preparation 1.

Step 5:[1-(Methylsulphonyl)-5,6-dihydro-1H-cyclobuta[f]indol-6-yl]methanol

[0110] A solution of 1.6 g of the product obtained in Step 4 in 20 ml oftetrahydrofuran is added dropwise to a suspension of 0.42 g of lithiumaluminium hydride in 7 ml of tetrahydrofuran maintained at 0° C. After20 minutes, the reaction mixture is hydrolysed with 0.3 ml of water,0.23 ml of 20% sodium hydroxide solution and then 1.05 ml of water.After removal of the salts by filtration, the filtrate is concentratedunder reduced presure to yield the expected product.

Step 6: 5,6-Dihydro-1H-cyclobuta[f]indol-6-ylmethanol

[0111] Starting from the compound of the above Step, the product isobtained in accordance with the procedure in Step 4 of Preparation 1.

Step 7: 2,3,5,6-Tetrahydro-1H-cyclobuta[f]indol-6-ylmethanol

[0112] Starting from the compound of the above Step, the product isobtained in accordance with the procedure in Step 5 of Preparation 1.The compound is isolated by chromatography on silica gel(dichloromethane/ethanol: 97/3).

PREPARATION 5: 2,3,6,7-Tetrahydro-1H-cyclobuta[g]indol-7-ylmethanol Step1: 6-Acetyl-1-benzocyclobutanecarbonitrile

[0113] A solution composed of 55.94 g of6-trifluoroacetyl-1-benzocyclobutanecarbonitrile in 600 ml of pyridineis purged with nitrogen for 15 minutes; 30.5 ml of triethylamine, 117.44ml of butyl vinyl ether, 2.25 g of 1,3-bis-(diphenylphosphino)propaneand 1.02 g of palladium acetate are added and the reaction mixture isheated at reflux for 2 hours. 400 ml of 1N hydrochloric acid are thenadded dropwise in the course of 1 hour and, after stirring for 3 hoursat ambient temperature, the reaction mixture is extracted with ether.The organic phases are washed, dried and concentrated to yield aresidue, which is purified by chromatography on silica gel(dichloromethane: 100%) allowing the expected product to be isolated.

[0114] Melting point: 55-59° C.

Step 2: 6-Hydroxyiminoethyl-1-benzocyclobutanecarbonitrile

[0115] 10.07 g of the product of Step 1 and 6.13 g of hydroxylaminehydrochloride in 200 ml of pyridine are stirred at ambient temperaturefor 19 hours. After removal of the pyridine by evaporation, the yellowoil obtained is taken up in dichloromethane and water. The organic phaseis removed, dried and concentrated, allowing the expected product to beisolated.

[0116] Melting point: 108-110° C.

Step 3: N-(1-Cyanobenzocyclobutan-6-yl)acetamide

[0117] 9.96 g of PCl₅ are added in four lots to a solution, cooled to 0°C., of 8.9 g of the product obtained in Step 2 in 160 ml of ether. Afterstirring for 2 hours at 0° C., the reaction mixture is brought toambient temperature for 12 hours and then poured into a water/icemixture and stirred for 20 minutes. After decanting and extracting withether, the combined organic phases are dried and then concentrated underreduced pressure to yield the expected product.

[0118] Melting point: <50° C.

Step 4: Ethyl 6-amino-1-benzocyclobutanecarboxylate

[0119] A stream of gaseous HCl is introduced until a solution of 5.04 gof the product obtained in Step 3 in 400 ml of anhydrous ethanol at 0°C. is saturated. The reaction mixture is then heated at reflux for 18hours. After concentrating the solvent, the residue is taken up in icedwater, rendered basic with a sodium carbonate solution and extractedwith dichloromethane. The organic phase is removed, dried andconcentrated to yield the expected product

Step 5: 2,3,6,7-Tetrahydro-1H-cyclobuta[g]indol-7-ylmethanol

[0120] Starting from the compound of the above Step, the product isobtained according to the procedures in Steps 2 to 7 of Preparation 4.

PREPARATION 6: 2,3,5,6Tetrahydro-1H-cyclobuta[f]indole-5-carbonitrile

[0121] The product is obtained in accordance with the procedure inPreparation 1, Steps 1 to 5, using as substrate in Step1-4-amino-1-benzocyclobutanecarbonitrile.

[0122] Melting point: 103-107° C.

PREPARATION 7: 2,3,5,6Tetrahydro-1H-cyclobuta[f]indol-5-ylmethanol

[0123] The product is obtained in accordance with the procedure inPreparation 4, Steps 1 to 7, using as substrate in Step 1 ethyl4-nitro-1-benzocyclobutanecarboxylate.

PREPARATION 8: Nicotinoyl azide

[0124] There are added to a suspension of 12.3 g of nicotinic acid in100 ml of dimethylformamide 14.2 ml of triethylamine and then, aftercooling to 0° C., 22 ml of diphenylphosphoryl azide in 50 ml ofdimethylformamide. After stirring for 2 hours, the reaction mixture ispoured onto ice. After extraction with ether, the organic phase iswashed with a NaHCO₃ solution, dried, and then concentrated to yield9.68 g of the expected product.

PREPARATION 9: Phenyl 6[(2-methyl-3-pyridyl)oxy]-3-pyridylcarbamate Step1: 6-[(2-Methyl-3-pyridyl)oxy]-3-pyridylamine

[0125] A solution of 14.35 g of tin chloride in 30 ml of concentratedhydrochloric acid is added to a mixture of 5 g of2-(2-methylpyrid-3-yloxy)-5-nitropyridine and the whole is heated atreflux for 1 hour. The reaction mixture is cooled and adjusted to basicpH by the addition of concentrated sodium hydroxide solution. After theremoval of a precipitate by filtration, the aqueous phase is extractedwith ethyl acetate. After conventional working up, the expected productis isolated in the form of a violet powder.

[0126] Melting point: 95-100° C. (M.K)

Step 2: Phenyl 6-[(2-methyl-3-pyridyl)oxy]-3-pyridylcarbamate

[0127] 3 ml of methyl chloroformate are added dropwise to a solution,maintained at −20° C., of 4.5 g of the product obtained in Step 1, 3.3ml of triethylamine and 180 ml of dichloromethane. After returning toambient temperature, the reaction mixture is washed with sodium hydrogencarbonate, dried and concentrated under reduced pressure. Chromatographyon silica gel of the residue (dichloromethane/ethanol/NH₄OH: 98/2/0.29)allows the expected product to be isolated.

EXAMPLE 1N-(3-Pyridyl)-2,3,5,6-tetrahydro-1H-cyclobuta[f]indole1-carboxamide

[0128] 7.4 g of the compound of Preparation 8 in 40 ml of toluene areheated at reflux for 2 hours 30 minutes, then cooled to ambienttemperature. 0.99 g of the product of Preparation 3 dissolved in 50 mlof dichloromethane are then added dropwise. After stirring for 18 hours,the reaction mixture is filtered and the filtrate is concentrated underreduced pressure. Chromatography on silica gel (dichloromethane/ethanol:95/5) allows isolation of the expected product, which is thenrecrystallised from ethanol.

[0129] Melting point: 178-180° C. (M.K)

EXAMPLE 26-(Hydroxymethyl)-N-(3-pyridyl)-2,3,5,6-tetrahydro-1H-cyclobuta[f]indole1-carboxamide

[0130] The product is obtained in accordance with the procedure inExample 1, using as substrate the compound of Preparation 4.

[0131] Melting point: 195-200° C. (M.K.)

EXAMPLE 36-Cyano-N-(3-pyridyl)-2,3,5,6-tetrahydro-1H-cyclobuta[f]indole-1-carboxamide

[0132] The product is obtained in accordance with the procedure inExample 1, using as substrate the compound of Preparation 1.

[0133] Melting point: 203-207° C. (M.K.)

EXAMPLE 45-Cyano-N-(3-pyridyl)-2,3,5,6-tetrahydro-1H-cyclobuta[f]indole-1-carboxamide

[0134] The product is obtained in accordance with the procedure inExample 1, using as substrate the compound of Preparation 6.

[0135] Melting point: 209-211° C. (M.K.)

EXAMPLE 55-(Hydroxymethyl)-N-(3-pyridyl)-2,3,5,6-tetrahydro-1H-cyclobuta[f]indole-1-carboxamide

[0136] The product is obtained in accordance with the procedure inExample 1, using as substrate the compound of Preparation 7.

[0137] Melting point: 167-173° C. (M.K.)

EXAMPLE 67-Cyano-N-(3-pyridyl)-1,2,6,7-tetrahydro-3H-cyclobuta[e]indole-3-carboxamide

[0138] The product is obtained in accordance with the procedure inExample 1, using as substrate the compound of Preparation 2.

[0139] Melting point: 203-205° C. (M.K.)

EXAMPLE 77-(Hydroxymethyl)-N-(3-pyridyl)-2,3,6,7-tetrahydro-1H-cyclobuta[g]indole-1-carboxamide

[0140] The product is obtained in accordance with the procedure inExample 1, using as substrate the compound of Preparation 5.

[0141] Melting point: 216-220° C. (M.K.)

EXAMPLE86-[(Dimethylamino)methyl]-6-(1-hydroxycyclohexyl)-N-(3-pyridyl)-2,3,5,6-tetrahydro-1H-cyclobuta[f]indole1-carboxamideStep 1:6-(1-Hydroxycyclohexyl)-2,3,5,6-tetrahydro-1H-cyclobuta[f]indole-6-carbonitrile

[0142] 4.1 g of the product obtained in Preparation 1 are dissolved in215 ml of tetrahydrofuran. The reaction mixture is cooled to −80° C. and19.25 ml of a 2.5M solution of n-butyllithium in hexane are added usinga push-syringe. When the addition is complete, stirring is carried outfor 20 minutes and then 6.2 ml of cyclohexanone are poured in in thecourse of 3 minutes. After contact at −80° C. for two hours, the wholeis allowed to return to ambient temperature, and 23 ml of a saturatedaqueous solution of ammonium chloride and also 135 ml of water areadded. After decanting, the organic phase is washed with a saturatedsodium chloride solution, dried and concentrated. The residue obtainedis solidified with isopropyl ether and filtered to obtain the desiredproduct, and the filtrate is purified by chromatography on silica gel(CH₂Cl₂/AcOEt: 90/10) in order to isolate an additional amount of theexpected product.

[0143] Melting point: 168-170° C.

Step 2:6-(1-Hydroxycyclohexyl)-1-(methylsulphonyl)-2,3,5,6-tetrahydro-1H-cyclobuta[f]indole-6-carbonitrile

[0144] 4 g of the product obtained in Step 1 are reacted under theconditions in Step 2 of Preparation 1.

Step 3:1-[6-(Aminomethyl)-1-(methylsulphonyl)-2,3,5,6-tetrahydro-1H-cyclobuta[f]indol-6-yl]cyclohexanol

[0145] 5.5 g of the product obtained in Step 2 are dissolved in 250 mlof a 3.6N solution of ammoniacal methanol containing 2 mg of Raneynickel. The reaction mixture is hydrogenated for 24 hours at 60° C.under a pressure of 30 bar. After filtration and removal of the solventby evaporation, the residue is taken up in dichloromethane, washed withwater until neutral, dried and concentrated to isolate the expectedproduct.

Step 4:1-[6-[(Dimethylamino)methyl]-1-(methylsulphonyl)-2,3,5,6-tetrahydro-1H-cyclobuta[f]indol-6-yl]cyclohexanol

[0146] 5.37 g of the amine obtained in Step 3 are dissolved in 130 ml ofacetonitrile. There are introduced into the solution, which has beencooled to 0° C., 2.9 g of sodium cyanoborohydride and 6.9 ml of a 37%fornmaldehyde solution in water, while maintaining the temperature at 0°C. After 20 hours' reaction at ambient temperature, the mixture ishydrolysed with 210 ml of 1N hydrochloric acid and then stirred for 3hours. The reaction mixture is washed with 30 ml of ether and thenrendered basic using 20% sodium hydroxide solution. The aqueous phase isextracted with dichloromethane. After drying and evaporation, theresidue is purified by chromatography on silica gel (CH₂Cl₂/EtOH: 95/5)to yield the expected product.

[0147] Melting point: 156-158° C. (M.K)

Step 5:1-{6-[(Dimethylamino)methyl]-2,3,5,6-tetrahydro-1H-cyclobuta[f]indol-6-yl}cyclohexanol

[0148] 3.75 g of the product obtained in Step 4 in 100 ml oftetrahydrofuran are added dropwise to 400 ml of liquid ammonia cooled to−50° C. 0.56 g of sodium are added in portions, and stirring is carriedout for 15 minutes. The reaction is terminated by the addition of 2.65 gof ammonium chloride. The whole is allowed to return to ambienttemperature to evaporate the ammonia, and is then taken up in water andextracted with ether. Drying, evaporation and recrystallisation fromacetonitrile are carried out to yield the expected product.

[0149] Melting point: 159-161° C. (M.K.)

Step 6:6-[(Dimethylamino)methyl]-6-(1-hydroxycyclohexyl)-N-(3-pyridyl)-2,3,5,6-tetrahydro-1H-cyclobuta[f]indole-1-carboxamide

[0150] The product is obtained in accordance with the procedure inExample 1, using as substrate the product obtained in Step 5.

[0151] Melting point: 207-209° C.

EXAMPLE 96-Cyano-6(phenylsulphanyl)-N-(3-pyridyl)-2,3,5,6-tetrahydro-1H-cyclobuta[f]indole-1-carboxamideStep 1:6-(Phenylsulphanyl)-2,3,5,6-tetrahydro-1H-cyclobuta[f]indole-6-carbonitrile

[0152] 15 ml of a 1.6N solution of n-butyllithium in hexane are added inthe course of 30 minutes to a solution, cooled to −70° C., of 2 g of theproduct of Preparation 1 dissolved in 40 ml of tetrahydrofuran, and then2.82 g of diphenyl sulphide dissolved in 8 ml of tetrahydrofuran arepoured in. The reaction mixture is slowly brought to ambienttemperature. After reaction for 2 hours, the mixture is poured into 1.2litres of a saturated ammonium chloride solution and then extracted withether. The combined organic phases are purified by acid-base exchange,allowing the expected product to be isolated.

Step 2:6-Cyano-6-(phenylsulphanyl)-N-(3-pyridyl)-2,3,5,6-tetrahydro-1H-cyclobuta[f]indole-1-carboxamide

[0153] 0.43 g of the product obtained in Step 1 are treated with 0.297 gof the compound of Preparation 8 in accordance with the proceduredescribed in Example 1, allowing the expected product to be obtained.

[0154] Melting point: 110-113° C. (M.K.)

EXAMPLE 106-Cyano-6-cyclohexyl-N-(3-pyridyl)-2,3,5,6-tetrahydro-1H-cyclobuta[f]indole-1-carboxamideStep 1:6-Cyclohexyl-2,3,5,6-tetrahydro-1H-cyclobuta[f]indole-6-carbonitrile

[0155] 15 ml of a 1.6N solution of n-butyllithium in hexane are added inthe course of 30 minutes to a solution, cooled to −70° C., of 2 g of theproduct of Preparation 1 dissolved in 20 ml of tetrahydrofuran. Aftercontact for 30 minutes, 2.17 ml of bromocyclohexane are poured in in thecourse of 25 minutes and the reaction mixture is progressively broughtto −20° C. and then poured into a saturated ammonium chloride solutionand finally extracted with ether. Purification on silica(dichloromethane/ethyl acetate: 95/5) yields the expected product in theform of an oil.

Step 2:6-Cyano-6-cyclohexyl-N-(3-pyridyl)-2,3,5,6-tetrahydro-1H-cyclobuta[f]indole-1-carboxamide

[0156] 0.33 g of the product obtained in Step 1 are treated with 0.25 gof the compound of Preparation 8 in accordance with the proceduredescribed in Example 1, allowing the expected product to be obtained.

[0157] Melting point: 224-227° C.

EXAMPLE 116-Cyclohexyl-N-(3-pyridyl)-2,3,5,6-tetrahydro-1H-cyclobuta[f]indole-1-carboxamideStep 1: 6-Cyclohexyl-2,3,5,6-tetrahydro-1H-cyclobuta[f]indole

[0158] A solution of 0.5 g of the product obtained in Step 1 of Example10 in 10 ml of anhydrous tetrahydrofuran and 0.11 ml of absolute ethanolare poured into 20 ml of liquid ammonia at a temperature of −78° C., andthen 0.15 g of sodium are introduced in portions. After contact for 30minutes at that temperature, the reaction mixture is treated with 0.83 gof ammonium chloride. After removal of the ammonia by evaporation, theresidue is taken up in a saturated solution of ammonium chloride andextracted with ether and the ethereal phases are washed, dried andconcentrated to yield the expected product.

Step 2:6-Cyclohexyl-N-(3-pyridyl)-2,3,5,6-tetrahydro-1H-cyclobuta[f]indole-1-carboxamide

[0159] 0.43 g of the product obtained in Step 1 are treated with 0.36 gof the compound of Preparation 8 in accordance with the proceduredescribed in Example 1, allowing the expected product to be obtained.

[0160] Melting point: 187-190° C. (M.K.)

EXAMPLE 126-Cyano-N-{6-[(2-methyl-3-pyridyl)oxy]-3-pyridyl}-6-(phenylsulphanyl)-2,3,5,6tetrahydro-1H-cyclobuta[f]indole-1-carboxamide

[0161] A mixture composed of 0.5 g of the product obtained in Example 9,0.6 g of the product of Preparation 9, 0.16 ml of triethylamine and 16ml of dimethylformamide is heated at 100° C. for 1 hour. After removalof the dimethylformamide by evaporation, the residue is taken up in 100ml of dichloromethane, washed with 10% sodium hydroxide solution, andwith water, and then dried and concentrated under reduced pressure toyield the desired product after purification on silica(dichloromethane/ethanol/NH₄OH: 98/2/0.4) and recrystallisation fromacetonitrile.

Pharmacological Study of the Compounds of the Invention EXAMPLE 13 VogelConflict Test

[0162] The test is carried out on male Wistar rats (IFFA-CREDO) weighingfrom 230 to 250 g, which are kept in groups of 4 on sawdust in cages inan animal house, with free access to food and drink, for 5 days beforethey are used, under the following conditions: temperature (21±1° C.),humidity (60±5%) and a 12 hour diurnal cycle (07:00 to 19:00 hours).

[0163] On the Monday following their arrival, the animals aretransferred to the experiment room where they stay until Friday, the dayof the test. For 4 days, from Monday to Thursday inclusive, the animalshave access to drink for only one hour per day (from 09:00 to 10:00hours).

[0164] On the day before the test, the animals are isolated from 15:00hours in cages, on grills, without either food or drink.

[0165] The test is carried out in a transparent plastics cage located ina soundproofed and ventilated enclosure. The cage has a chrome steelfloor. The metal tip of the bottle containing the drink enters the cageat a height of 6 cm above the metal floor. The floor and the tip of thebottle are connected by electric cables to an apparatus which recordsthe licks of the animal and controls the administration of electricshocks. The apparatus is so regulated that the animal receives anelectric shock (between tip and metal floor) every 20 licks of the tip.

[0166] On the day of the test, the animal is given an injection (s.c.)of physiological serum (control) or of the test product 30 minutesbefore being placed in the test cage. The session begins as soon as theanimal has carried out 20 licks and received a first electric shock(duration 0.5 seconds, intensity 0.300 mA). For a period of 3 minutes,the animal receives an electric shock each time it carries out 20 licks.

[0167] The results are the numbers of licks and of shocks received bythe animal during the 3 minutes of the test.

[0168] The numbers of licks and of shocks received by the treatedanimals are compared with those of the control animals by varianceanalysis, followed by a Dunnett's test with p<0.05. An anxiolyticproduct increases the number of licks and of shocks received by theanimal compared with the controls. For information only, the averagenumber of licks not punished in the animals which have been made thirstyis 674.9±44.5 (N=7) over 3 minutes.

[0169] The effectiveness of a product is expressed by the minimumeffective dose (MED), that is to say, the lowest dose producing asignificant difference compared with the controls. That dose is 2.5mg/kg s.c. for the product of Example 1. Results for the product ofExample n° 1 Punished licks Doses mg/kg, s.c. (1 shock/20 licks) N 0142.7 ± 31.9  10 0.63 197.5 ± 59.5  8 2.5 560.1 ± 67.0* 8 10.0 499.3 ±95.3* 7

EXAMPLE 14 Marble-burying Test in the Mouse

[0170] This test allows evaluation of the capacity of pharmacologicalagents to inhibit the spontaneous marble-burying behaviour of mice, theinhibition being predictive of antidepressant and/or anti-impulsiveaction. Male mice of the NMRI strain (Iffa-Credo, l'Arbresle, France)weighing from 20 to 25 g on the day of the experiment are placedindividually in Macrolon boxes (30×18×19 cm) containing 5 cm of sawdustand covered with a perforated plexiglass plate. Twenty four “tiger'seye” glass marbles are evenly distributed on the sawdust at theperiphery of the box. At the end of 30 minutes' free exploration, theanimals are removed from the box and the number of buried marbles iscounted.

[0171] By way of example, the MED (minimum effective dose) for theproduct of Example 1 is 2.5 mg/kg s.c.

EXAMPLE 15 Pharmaceutical Composition: Tablets

[0172] Formulation for the preparation of 1000 tablets each comprising 5mg of active ingredient

[0173] compound of Example 1 . . . 5 g

[0174] hydroxypropyl methylcellulose . . . 5 g

[0175] wheat starch . . . 10 g

[0176] lactose . . . 100 g

[0177] magnesium stearate . . . 2 g

1. A compound selected from those of formula (I):

wherein n represents integer from 0 to 6, R₁ represents a group selectedfrom hydrogen, hydroxy, cyano, linear or branched (C₁-C₆)alkoxy, linearor branched (C₁-C₆)alkoxycarbonyl, carboxy, aminocarbonyl (amino moietyoptionally being substituted by one or two, identical or different,groups selected from linear or branched (C₁-C₆)alkyl, aryl, andaryl-(C₁-C₆)alkyl in which alkyl may be linear or branched), and NR₄R₅wherein R₄ and R₅, which may be identical or different, represent agroup selected from linear or branched (C₁-C₆)alkyl, aryl,aryl-(C₁-C₆)alkyl in which alkyl may be linear or branched, heteroaryl,heteroaryl-(C₁-C₆)alkyl in which alkyl may be linear or branched,cycloalkyl, cycloalkyl-(C₁-C₆)alkyl in which alkyl may be linear orbranched, linear or branched (C₂-C₆)alkenyl, and linear or branched(C₂-C₆)alkynyl, R₂ represents a group selected from hydrogen, linear orbranched (C₁-C₆)alkyl, hydroxymethyl, a group of formula

 and —U—V—W wherein: T represents monocyclic or polycyclic(C₃-C₁₂)cycloalkyl, it being possible for one of carbon of cycloalkyloptionally to be replaced by a group selected from oxygen, selenium,S(O)_(p) wherein p represents integer from 0 to 2 inclusive, SiR₆R₇wherein R₆ and R₇, which may be identical or different, represent linearor branched (C₁-C₆)alkyl, U represents a bond or methylene, V representsa bond, oxygen, or S(O)_(q) wherein q is integer 0 to 2 inclusive, and Wrepresents a group selected from aryl, aryl-(C₁-C₆)alkyl in which alkylmay be linear or branched, cycloalkyl, and cycloalkyl-(C₁-C₆)alkyl inwhich alkyl may be linear or branched, and R₃ represents a groupselected from hydrogen, linear or branched (C₁-C₆)alkyl, aryl, andheteroaryl, its isomers, and also addition salts thereof with apharmaceutically-acceptable acid or base, wherein: aryl is to beunderstood as a group selected from phenyl, biphenyl, naphthyl,dihydronaphthyl, tetrahydronaphthyl, indanyl, indenyl, andbenzocyclobutyl, each of which groups is optionally substituted by oneor more, identical or different, groups selected from halogen, linear orbranched (C₁-C₆)alkyl, hydroxy, linear or branched (C₁-C₆)alkoxy, nitro,cyano, linear or branched (C₁-C₆)trihaloalkyl, amino, monoalkylamino,di-(C₁-C₆)alkylamino in which alkyl may be linear or branched,(C₁-C₆)trihaloalkoxy in which alkoxy may be linear or branched,amino-(C₁-C₆)alkylaminocarbonyl (nitrogen of each of amino moietiesoptionally being substituted by, identical or different, linear orbranched (C₁-C₆)alkyl), pyridyl, pyridyloxy, and pyridyloxymethyl, thelatter three groups optionally being substituted by linear or branched(C₁-C₆)alkyl, heteroaryl is to be understood as aromatic monocyclicsystem, or bicyclic system in which one of the rings is aromatic and theother ring is aromatic or partially hydrogenated, having from 5 to 12ring members, and containing one, two, or three identical or differenthetero atoms selected from oxygen, nitrogen, and sulphur, each of thegroups optionally being substituted by one or more, identical ordifferent, groups selected from the substituents described for aryldefined above, and cycloalkyl is to be understood as mono- orpoly-cyclic system having from 3 to 12 ring members and optionallycontaining one or more unsaturations, wherein unsaturations do notconfer aromatic character to the said ring system.
 2. A compound ofclaim 1, characterised in that R₂ represents hydrogen, its isomers, andalso addition salts thereof with a pharmaceutically-acceptable acid orbase.
 3. A compound of claim 1, characterised in that R₂ represents agroup of formula

wherein T is as defined for formula (I), n is 1, and R₁ representscyano, or amino optionally substituted by one or two, identical ordifferent, groups selected from linear or branched (C₁-C₆)alkyl, andaryl-(C₁-C₆)alkyl in which alkyl may be linear or branched, its isomers,and also addition salts thereof with a pharmaceutically-acceptable acidor base.
 4. A compound of claim 1, characterised in that n is 0, R₁represents hydrogen, or cyano, and R₂ represents hydrogen, its isomers,and also addition salts thereof with a pharmaceutically-acceptable acidor base.
 5. A compound of claim 1, characterised in that n is 0, R₁represents hydrogen, or cyano, and R₂ represents a group of formula—U—V—W wherein U represents single bond, V represents a group of formulaS(O)_(p) wherein p is as defined for formula (I), and W represents aryl,its isomers, and also addition salts thereof with apharmaceutically-acceptable acid or base.
 6. A compound of claim 1,characterised in that R₃ represents heteroaryl, its isomers, and alsoaddition salts thereof with a pharmaceutically-acceptable acid or base.7. A compound of claim 1, characterised in that R₃ represents pyridyl,its isomers, and also addition salts thereof with apharmaceutically-acceptable acid or base.
 8. A compound of claim 1 thatis selected from:N-(3-pyridyl)-2,3,5,6-tetrahydro-1H-cyclobuta[f]indole-1-carboxamide,5-cyano-N-(3-pyridyl)-2,3,5,6-tetrahydro-1H-cyclobuta[f]indole-1-carboxamide,6-cyano-N-(3-pyridyl)-2,3,5,6-tetrahydro-1H-cyclobuta[f]indole-1-carboxamide,6-(hydroxymethyl)-N-(3-pyridyl)-2,3,5,6-tetrahydro-1H-cyclobuta[f]indole-1-carboxamide,5-(hydroxymethyl)-N-(3-pyridyl)-2,3,5,6-tetrahydro-1H-cyclobuta[f]indole-1-carboxamide,7-cyano-N-(3-pyridyl)-1,2,6,7-tetrahydro-3H-cyclobuta[e]indole-3-carboxamide,7-(hydroxymethyl)-N-(3-pyridyl)-2,3,6,7-tetrahydro-1H-cyclobuta[g]indole-1-carboxamide,6-[(dimethylamino)methyl]-6-(1-hydroxycyclohexyl)-N-(3-pyridyl)-2,3,5,6-tetrahydro-1H-cyclobuta[f]indole-1-carboxamide,6-cyano-6-(phenylsulphanyl)-N-(3-pyridyl)-2,3,5,6-tetrahydro-1H-cyclobuta[f]indole-1-carboxamide,6-cyano-6-cyclohexyl-N-(3-pyridyl)-2,3,5,6-tetrahydro-1H-cyclobuta[f]indole1-carboxamide,6-cyclohexyl-N-(3-pyridyl)-2,3,5,6-tetrahydro-1H-cyclobuta[f]indole-1-carboxamide,and6-cyano-N-{6-[(2-methyl-3-pyridyl)oxy]-3-pyridyl}-6-(phenylsulphanyl)-2,3,5,6-tetrahydro-1H-cyclobuta[f]indole-1-carboxamide,its isomers, and also addition salts thereof with a pharmaceuticallyacceptable acid or base.
 9. A method for treating a living bodyafflicted with a disease like anxiety, panic attacks,obsessive-compulsive disorders, phobias, impulsive disorders, drugabuse, cognitive disorders, psychoses, depression and mood disorders,comprising the step of administering to the living body an amount of acompound of claim 1 which is effective for alleviation of saidconditions.
 10. A pharmaceutical composition useful in the claim 9method comprising as active principle an effective amount of a compoundas claimed in claim 1, together with one or morepharmaceutically-acceptable excipients or vehicles.